title: Interplay of Phosphorylated Apoptosis Repressor with CARD, Casein Kinase-2 and Reactive Oxygen Species in Regulating Endothelin-1-Induced Cardiomyocyte Hypertrophy.
abstract: OBJECTIVE
  The role of the Apoptosis repressor with caspase recruitment domain (ARC) in apoptosis and in certain hypertrophic responses has been previously investigated, but its regulation of Endothelin-1 induced cardiac hypertrophy remains unknown. The present study discusses the inhibitory role of ARC against endothelin-induced hypertrophy.
  
  
  RESULTS
  In present study Endothelin treated cardiomyocytes were used as a hypertrophic model, that were subsequently treated with adenovirus ARC and its mutant at different multiplicity of infections. Casein-kinase-2 inhibitors were used to produce dephosphorylated ARC and to study its effect on hypertrophy. Hypertrophy was assessed by cell surface area measurement, Atrial-natriuretic-Factor mRNA analysis and total protein assay. Reactive oxygen species analysis was carried out using the dichlorofluorescin-diacetate (DCFH-DA) assay. Over expression of ARC significantly inhibits Endothelin-induced cardiomyocyte hypertrophy. The nonphosphorylated mutant ARC (T149 A) remained unable to control endothelin-induced hypertrophy, suggesting a vital role for ARC phosphorylation in regulation of its activity. Sensitization study has been carried out to check the role of endogenous ARC using casein-kinase inhibitors. Finally, the significant role of ARC in regulating reactive oxygen species -mediated control of endothelin induced hypertrophy has also been assessed. Conclusion : Conclusively, present study showed the vital and potential therapeutic interventional role of ARC in preventing endothelin-1-induced cardiomyocyte hypertrophy. The regulation of hypertrophic pathway by ARC relies on blunting the reactive oxygen species attack. This study further suggests a mediatory role of casein-kinase-2 in Endothelin-induced hypertrophy, mainly through its phosphorylation of ARC.
authors.affiliation: Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People's Republic of China ; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, 45320, Islamabad, Pakistan.
authors.forename: Iram
authors.initials: I
authors.lastname: Murtaza
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.forename: Sobia
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Qamar
authors.initials: Q
authors.lastname: Javed
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Li
keywords: Apoptosis repressor with caspase recruitment dom- ain; Cardimyocyte hypertro- phy; Endothelin-1; Protein kinase CK2; Reactive oxygen species